Side Chain Optimization Remarkably Enhances the in Vivo Stability of 18F-Labeled Glutamine for Tumor Imaging
Similar to glycolysis, glutaminolysis acts as a vital energy source in tumor cells, providing building blocks for the metabolic needs of tumor cells. To capture glutaminolysis in tumors, 18F-(2S,4R)4-fluoroglutamine ([18F]FGln) and 18F-fluoroboronoglutamine ([18F]FBQ) have been successfully developed for positron emission tomography (PET) imaging, but these two molecules lack stability, resulting in undesired yet significant bone uptake. In this study, we found that [18F]FBQ-C2 is a stable Gln PET tracer by adding two more methylene groups to the side chain of [18F]FBQ. [18F]FBQ-C2 was synthesized with a good radiochemical yield of 35% and over 98% radiochemical purity. [18F]FBQ-C2 showed extreme stability in vitro, and no defluorination was observed after 2 h in phosphate buffered saline at 37 °C. The competitive inhibition assay results indicated that [18F]FBQ-C2 enters cells via the system ASC and N, similar to natural glutamine, and can be transported by tumor-overexpressed ASCT2. PET imaging and biodistribution results indicated that [18F]FBQ-C2 is stable in vivo with low bone uptake (0.81 ± 0.20% ID/g) and can be cleared rapidly from most tissues. Dynamic scan and pharmacokinetic studies using BGC823-xenograft-bearing mice revealed that [18F]FBQ-C2 accumulates specifically in tumors, with a longer half-life (101.18 ± 6.50 min) in tumor tissues than in other tissues (52.70 ± 12.44 min in muscle). Biodistribution exhibits a high tumor-to-normal tissue ratio (4.8 ± 1.7 for the muscle, 2.5 ± 1.0 for the stomach, 2.2 ± 0.9 for the liver, and 17.8 ± 8.4 for the brain). In conclusion, [18F]FBQ-C2 can be used to perform high-contrast Gln imaging of tumors and can serve as a PET tracer for clinical research.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2019 |
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| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:16 |
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| Enthalten in: |
Molecular pharmaceutics - 16(2019), 12 vom: 02. Dez., Seite 5035-5041 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Chen, Junyi [VerfasserIn] |
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| Links: |
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| Themen: |
0RH81L854J |
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| Anmerkungen: |
Date Completed 24.07.2020 Date Revised 24.07.2020 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1021/acs.molpharmaceut.9b00891 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM302754482 |
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| 520 | |a Similar to glycolysis, glutaminolysis acts as a vital energy source in tumor cells, providing building blocks for the metabolic needs of tumor cells. To capture glutaminolysis in tumors, 18F-(2S,4R)4-fluoroglutamine ([18F]FGln) and 18F-fluoroboronoglutamine ([18F]FBQ) have been successfully developed for positron emission tomography (PET) imaging, but these two molecules lack stability, resulting in undesired yet significant bone uptake. In this study, we found that [18F]FBQ-C2 is a stable Gln PET tracer by adding two more methylene groups to the side chain of [18F]FBQ. [18F]FBQ-C2 was synthesized with a good radiochemical yield of 35% and over 98% radiochemical purity. [18F]FBQ-C2 showed extreme stability in vitro, and no defluorination was observed after 2 h in phosphate buffered saline at 37 °C. The competitive inhibition assay results indicated that [18F]FBQ-C2 enters cells via the system ASC and N, similar to natural glutamine, and can be transported by tumor-overexpressed ASCT2. PET imaging and biodistribution results indicated that [18F]FBQ-C2 is stable in vivo with low bone uptake (0.81 ± 0.20% ID/g) and can be cleared rapidly from most tissues. Dynamic scan and pharmacokinetic studies using BGC823-xenograft-bearing mice revealed that [18F]FBQ-C2 accumulates specifically in tumors, with a longer half-life (101.18 ± 6.50 min) in tumor tissues than in other tissues (52.70 ± 12.44 min in muscle). Biodistribution exhibits a high tumor-to-normal tissue ratio (4.8 ± 1.7 for the muscle, 2.5 ± 1.0 for the stomach, 2.2 ± 0.9 for the liver, and 17.8 ± 8.4 for the brain). In conclusion, [18F]FBQ-C2 can be used to perform high-contrast Gln imaging of tumors and can serve as a PET tracer for clinical research | ||
| 650 | 4 | |a Journal Article | |
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| 700 | 1 | |a Wang, Chunhong |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Mengxin |e verfasserin |4 aut | |
| 700 | 1 | |a Han, Yuxiang |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Zhibo |e verfasserin |4 aut | |
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